Deletion of Alox15 improves kidney dysfunction and inhibits fibrosis by increased PGD₂ in the kidney

Background: Lipid-metabolizing enzymes and their metabolites affect inflammation and fibrosis, but their roles in chronic kidney disease (CKD) have not been completely understood. Methods: To clarify their role in CKD, we measured the mRNA levels of major lipid-metabolizing enzymes in 5/6 nephrectomized (Nx) kidneys of C57BL/6 J mice. Mediator lipidomics was performed to reveal lipid profiles of CKD kidneys. Results: In 5/6 Nx kidneys, both mRNA and protein levels of Alox15 were higher when compared with those in sham kidneys. With respect to in situ hybridization, the mRNA level of Alox15 was higher in renal tubules of 5/6 Nx kidneys. To examine the role of Alox15 in CKD pathogenesis, we performed 5/6 Nx on Alox15^−/− mice. Alox15^−/− CKD mice exhibited better renal functions than wild-type mice. Interstitial fibrosis was also inhibited in Alox15^−/− CKD mice. Mediator lipidomics revealed that Alox15^−/− CKD mouse kidneys had significantly higher levels of PGD₂ than the control. To investigate the effects of PGD₂ on renal fibrosis, we administered PGD₂ to TGF-β1-stimulated NRK-52E cells and HK-2 cells, which lead to a dose-dependent suppression of type I collagen and αSMA in both cell lines. Conclusion: Increased PGD₂ in Alox15^−/− CKD mouse kidneys could inhibit fibrosis, thereby resulting in CKD improvement. Thus, Alox15 inhibition and PGD₂ administration may be novel therapeutic targets for CKD.